A new size exclusion chromatographic procedure for determination of complexation of macromolecules with low molar mass substances (such as preferential solvation or drug-protein-binding) was proposed. The method is based on the assessment of system peaks formed as result of differences between eluent composition and bulk solvent composition due to the complexation within the initial sample solution. The composition of the eluent, which contains the same components as the sample solvent, is adjusted in such a way that the system peak disappears. Under these circumstances the bulk solvent composition equals to the eluent composition and the former can be easily calculated. This procedure was tested by measuring the preferential solvation in a model system polystyrene plus toluene plus methanol and by comparing the result with the data obtained with two other chromatographic methods.